Aging is the greatest risk factor for the development of Alzheimer's disease and related neurodegenerative conditions. There is increasing evidence that age-associated changes in metabolism play a major role in the onset or progression of these diseases. Both aging and Alzheimer's disease are associated with higher glucose accumulation and its reduced usage in the brain. While correlative data suggest that impaired glucose metabolism promotes Alzheimer's disease, the mechanisms causing these impairments are poorly understood. We recently identified profound age-related changes in the expression of genes associated with glucose metabolism in the heads of a model organism, fruit fly Drosophila melanogaster. Our preliminary NMR study demonstrated age-dependent increase in glucose in fly heads suggesting metabolic dysregulation similar as occurs in Alzheimer's disease. We will take advantage of transgenic flies with Alzheimer's like symptoms to perform mechanistic studies on the links between energy metabolism and neurodegeneration. Our overall aim is to understand factors that impair neuronal energy metabolism in aging and Alzheimer's disease models. Results of these studies may help to reveal ways to prevent or delay neurodegeneration and identify novel avenues for prevention and therapeutic intervention in Alzheimer's disease. We propose three specific aims. 1) Elucidate functional significance of age-related changes in the expression of metabolic genes and insulin signaling in causing neurodegeneration. 2) Determine changes in metabolomic profile in Alzheimer's disease models and investigate how they are controlled. 3) Integrate transcriptomic and metabolomic data to detect putative neurodegeneration-preventing pathways and test functional role of these pathways using genetic and pharmacological approaches. Taken together, proposed experiments will help to reveal mechanistic links between age-related changes in energy metabolism and Alzheimer's disease.